The renin-angiotensin system mediates changes in vascular structure and function in hypertension and[unreadable] probably other pathophysiological conditions. Angiotensin II (Ang II) is known to produce oxidative stress, but[unreadable] little is known about mechanisms that protect the vasculature from Ang II. The overall goal of this project is to[unreadable] define molecular mechanisms that protect blood vessels from oxidative stress and endothelial dysfunction[unreadable] produced by Ang II.[unreadable] Components of the inflammatory response are activated within the vessel wall in many diseases including[unreadable] hypertension. Ang II activates multiple inflammatory mechanisms within vascular cells. Although emerging[unreadable] evidence suggests a major protective role for the anti-inflammatory cytokine interleukin-10 (IL-10) in vascular[unreadable] biology, nothing is known regarding a potential protective role for IL-10 in hypertension. Our first Aim is to[unreadable] use gene targeted mice to examine the role of IL-10 in oxidative stress and vascular dysfunction produced[unreadable] by Ang II.[unreadable] Although oxidative stress appears to play a key role in hypertension, very little is known about the[unreadable] functional importance of superoxide dismutase (SOD) isoforms in hypertension. The manganese isoform of[unreadable] SOD (Mn-SOD) is expressed in relatively high levels in endothelium and is increased in hypertension and[unreadable] inflammation, but the functional importance of this expression is completely unknown. Our second Aim is to[unreadable] use Mn-SOD deficient and transgenic mice to examine the role of Mn-SOD in the vascular oxidative stress[unreadable] produced by Ang II.[unreadable] Recent data suggest that iNOS may be an important mediator of vascular dysfunction. iNOS is expressed[unreadable] in vascular cells in response to inflammatory stimuli and Ang II. In our third Aim, we will use iNOS deficient[unreadable] mice to examine the hypothesis that expression of iNOS contributes to oxidative stress and endothelial[unreadable] dysfunction in response to Ang II.[unreadable] We have obtained preliminary data that support these hypotheses. Our focus on mechanisms of oxidative[unreadable] stress and endothelial dysfunction seems appropriate considering that endothelial dysfunction has a major[unreadable] impact on the vessel wall and has emerged as an independent predictor of clinical events. Studies in this[unreadable] project should provide new insight into mechanisms of vascular protection against Ang II including[unreadable] inflammatory related mechanisms in hypertension. The studies fit well within several major themes of this[unreadable] program - oxidative stress, inflammation, and vascular dysfunction.